Pyroptosis in Triple-Negative Breast Cancer: From Inflammasome Signaling to Tumor Immune Remodeling and Translational Therapeutic Strategies.

Abstract

Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype marked by molecular heterogeneity, immune evasion, limited actionable targets, and variable responses to immune-based therapy. Pyroptosis, a gasdermin-mediated inflammatory form of regulated cell death, may link tumor-cell injury to remodeling of the tumor immune microenvironment (TIME). However, its role in TNBC should not be interpreted as uniformly antitumor. Instead, pyroptotic signaling represents a context-dependent inflammatory process shaped by inflammasome activation, gasdermin cleavage, cellular source, subcellular localization, cytokine release, hypoxia, stromal restriction, immune-cell composition, and membrane-repair capacity. Transient and spatially restricted tumor-cell pyroptosis may support antigen release, dendritic-cell activation, and cytotoxic lymphocyte recruitment, whereas persistent or poorly localized activation may amplify myeloid inflammation, fibrosis, immune exclusion, tissue injury, and inflammatory toxicity. This review critically examines pyroptosis-TIME crosstalk in TNBC, prioritizing TNBC and breast cancer evidence while using non-breast cancer findings only as mechanistic comparators when they clarify conserved inflammasome or gasdermin biology. We summarize canonical and non-canonical inflammasome pathways, gasdermin regulation, apoptosis-pyroptosis crosstalk, immune-subset remodeling, hypoxic and stromal constraints, and preclinical therapeutic approaches aimed at controlled pyroptosis induction. By distinguishing direct TNBC evidence from extrapolation and emphasizing safety, biomarkers, and validation gaps, this review provides an evidence-graded framework for evaluating pyroptosis as a potential but still investigational immunomodulatory strategy in TNBC.